Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice

Diabetes. 2007 Apr;56(4):1025-33. doi: 10.2337/db06-0883. Epub 2007 Jan 17.

Abstract

Stimulation of nitric oxide-cGMP signaling results in vascular relaxation and increased muscle glucose uptake. We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 inhibitor sildenafil improves energy balance and enhances in vivo insulin action in a mouse model of diet-induced insulin resistance. High-fat-fed mice treated with sildenafil plus L-arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, uncoupling protein-1 levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil plus L-arginine or sildenafil alone increased arterial cGMP levels but did not adversely affect blood pressure or cardiac morphology. Sildenafil treatment, with or without l-arginine, resulted in lower fasting insulin and glucose levels and enhanced rates of glucose infusion, disappearance, and muscle glucose uptake during a hyperinsulinemic (4 mU x kg(-1) x min(-1))-euglycemic clamp in conscious mice. These effects occurred without an increase in activation of muscle insulin signaling. An acute treatment of high fat-fed mice with sildenafil plus l-arginine did not improve insulin action. These results show that phosphodiesterase-5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animal Feed
  • Animals
  • Arginine / pharmacology
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Blood Pressure / drug effects
  • Body Composition / drug effects
  • Dietary Fats*
  • Echocardiography
  • Energy Metabolism / drug effects*
  • Feeding Behavior / drug effects
  • Glucose Clamp Technique
  • Insulin / pharmacology
  • Insulin / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Muscle / drug effects
  • Mitochondria, Muscle / metabolism
  • Piperazines / pharmacology*
  • Purines / pharmacology
  • Sildenafil Citrate
  • Sulfones / pharmacology*
  • Vasodilator Agents / pharmacology*

Substances

  • Blood Glucose
  • Dietary Fats
  • Insulin
  • Piperazines
  • Purines
  • Sulfones
  • Vasodilator Agents
  • Arginine
  • Sildenafil Citrate